Fluid dispensing device with a flow detector

ABSTRACT

A portable therapeutic fluid delivery device with a flow detector comprising a heating element and two temperature sensors is presented. Upon activation of the heating element, a flow condition of the fluid inside the delivery tube is determined based on a signal provided by the temperature sensors. A temperature gradient within the therapeutic fluid is detected. The determined flow condition can be one of: air bubbles within the delivery tube, occlusion within the delivery tube, or leakage within the delivery tube. The device can have two parts, for example, a reusable part and a disposable part. Upon pairing of these parts, the heating element and the temperature sensors touch the delivery tube.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/940,661, filed Nov. 24, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/872,938, filed Apr. 29, 2013, now U.S. Pat. No.9,227,010, issued Jan. 5, 2016, which is a continuation ofPCT/EP2011/005491, filed Oct. 29, 2011, which is based on and claimspriority to U.S. Provisional Application Ser. No. 61/408,941, filed Nov.1, 2010, which is hereby incorporated by reference.

BACKGROUND

The present disclosure generally relates to systems, devices, andmethods for dispensing of therapeutic fluid and, in particular, to adevice with a flow sensor or flow detector as well as to methods thatmakes use of such sensors or flow detectors.

Medical treatment of several illnesses requires continuous or periodicdrug infusion into various body compartments through subcutaneous andintra-venous injections. Diabetes mellitus (DM) patients, for example,require the administration of varying amounts of insulin throughout theday to control the patients' glucose levels. In recent years, ambulatoryportable Continuous Subcutaneous Insulin Infusion (hereinafter “CSII”)pumps have emerged as a superior alternative to the use of multipledaily injections (hereinafter “MDI”) of insulin, initially for Type 1diabetes patients, and subsequently for Type 2 diabetes patients. Thesepumps, which deliver insulin at a continuous or periodic basal rate, aswell as in bolus volumes, were developed to free patients from repeatedself-administered injections, and to allow them to maintain anear-normal daily routine. Both basal and bolus volumes have to bedelivered in precise doses, based on individual prescription, because anoverdose or under-dose of insulin could be fatal. In the context of thepresent disclosure. “continuous delivery” includes a quasi-continuousdelivery where small drug amounts are delivered in time intervals oftypically some minutes, resulting in the pharmacological effect beingsubstantially identical to a steady continuous delivery.

Insulin administration of basal and bolus doses is dependent on bodyglucose levels. Diabetes patients generally monitor their glucose levelsand adjust insulin dosing accordingly. Glucose levels may be monitoredby using blood-sensitive test strips (obtaining a blood sample throughfinger pricking), or by using removable insertable subcutaneous sensors.Insulin pumps can receive glucose measurements from glucose monitorseither manually (inputting numbers with a keypad) or by automaticallycommunicating (e.g., wirelessly) glucose readings from a remote glucosemonitor.

Some portable infusion pumps include “pager-like” devices, where such apager-like device includes a reservoir contained within the devicehousing. These devices are provided with a tube for delivering insulinfrom the pump which is, for example, attached to a patient's belt to aremote insertion site. The tubing length is in a range of typically 30cm to 1.5 m. Pumping is achieved, for example, by linear movement of apiston/plunger within a reservoir in a syringe-like way, forcing fluidto be expelled from the reservoir to the outlet port. Aprocessor-controlled motor and gear arrangement provides controlledrotational motion that is converted to linear movement by a rotation ofa nut over a plunger rod drive screw.

Both basal and bolus volumes delivered in these “pager-like” devices aretypically controlled via a set of buttons provided on the device. A userinterface screen is typically provided on the device housing to providethe user with information about fluid delivery status, to program flowdelivery, and to provide alerts and alarms. These devices represent asignificant improvement over a regiment based on multiple dailyinjections, but, nevertheless, suffer from several drawbacks, amongwhich are the large size and weight of such devices, their long deliverytubing, and lack of discreetness.

To avoid the consequences of comparatively long tubing for connectingpump and cannula, a new concept, an alternative architecture wasproposed. This architecture is based on a remote controlled skinadherable device with a housing having a bottom surface adapted forcontact with the patient's skin, a reservoir disposed within thehousing, and an injection needle in communication with the reservoir. Inthese devices, the user interface is provided as a separate remotecontrol unit that contains operating buttons and a screen to providefluid delivery status, to program flow delivery, to provide alerts andalarms, and the like. Corresponding devices still have severallimitations, including their heavy and bulky configuration, and therelative high cost resulting from their use due to the fact that thedevices have to be replaced after several days (e.g., 2-3 days). Anotherdrawback associated with this type of skin adherable devices relates tothe required remote control. The user is generally totally dependent onthe remote control unit and cannot initiate bolus delivery or operatethe device if the remote control unit is not at hand, is lost ormalfunctions.

A general limitation of current insulin pump devices is their lack offlow feedback. There is typically no monitoring or supervision ofinsulin flow within the delivery path after insulin is expelled from thereservoir outlet port by, for example, a plunger/piston linear movement,resulting in typical defects and/or hazardous situations, such asocclusions, air bubbles, or leakage being detected only with a largetime delay of typically several hours. In dependence of the specificdesign, some of these situations may not be detected at all by thedevice.

In addition, the required insulin volume (dose) administration isachieved by programmed timing of motor operation, and counting motor orgear revolution with an encoder. This revolution is converted to aproportional linear movement of the drive screw and plunger (motor gearrevolution reduction ratio is a fixed number). The distance ofplunger/piston linear movement may be derived from the motor and gearnumber of revolutions and pitch of the drive screw and is proportionalto the administered volume according to the drug reservoir crosssection. Delivery accuracy is accordingly dependent on the precision ofgears' cogwheels and drive screw pitch accuracies as well as theaccuracy of the reservoir cross section. Slight deviations of thoseinfluence factors, resulting, e.g. from manufacturing and/or assemblytolerances as well as from operation wear-and-tear can affect theprecision of linear movement, and consequently affect delivery accuracy.Furthermore, failures of the motor revolution counter (encoder) cancause uncontrolled motor operation, and consequently cause over- orunder insulin delivery. In some cases, a long time delay for detectingdefects or hazards or an over- or under delivery may result in seriousmedical complications, both short term and/or long/term.

A known problem of current insulin pumps both of the skin securable orpager type is the higher occurrence of severe high blood sugar eventsand diabetes ketoacidosis (DKA). DKA is a potentially life-threateningcomplication in patients with diabetes mellitus and results from anabsolute or relative shortage of insulin (under or no insulin delivery).In response to glucose deprivation the body switches to burning fattyacids and producing acidic ketone bodies that cause most of the symptomsand complications. The main reasons for insulin under-delivery andconsequently DKA in diabetes pump users are the occurrence of occlusionin the insulin path, air bubbles, and leakage. Occlusions occur whensomething blocks the infusion line. The causes can be manifold: a kinkin the line, insulin crystallization, deposits of fibrin, blood clot,lipid residues, and the like. Insulin path occlusion can be detected incurrent pumps by monitoring pressure or torque readings from part of theinsulin pump drive train (pulses generated in the processor to operatethe motor). The patient is notified with an alarm when any readingexceeds a predetermined threshold.

Another implementation for detecting an occlusion in a fluid deliverytube is based on a detection of tube's radial expansion. The expansionis caused by an elevation of an upstream pressure that is caused by adownstream occlusion. Various components may be used to measure tuberadial expansion, including a magnet sensitive element, resilientdiaphragm, and others. In one example, an alarm is triggered by a pairof pressure sensors located at two different places along the insulinflow passage in the pump. In another example, an occlusion detectordetects alteration in the shape of the insulin delivery tube.

In some of these occlusion detectors there, is a long lag time betweenthe occurrence of occlusion and the detection of the occlusion (andalarm activation). Pressure buildup within the delivery path is usuallyvery slow at low delivery rates typically used in insulin pump. Forexample, in one type of a commercial pump, occlusion is triggered by anaverage of 2.77 units of “missed insulin” with a typical time beforealarm at a basal delivery rate of 0.05 U/h being 59.2 hours. Thus, froma practical perspective, this occlusion detector may not be able toprevent severe hyperglycemia and/or DKA, which usually occur only a fewhours (e.g., 3-4 hours) after occurrence of occlusion.

Furthermore, existences of air bubbles in any medication infusion tubingcan cause under-delivery. In portable ambulatory insulin pumps,especially at low programmed delivery rates, air bubbles can result incessation of insulin administration for many hours and may consequentlyresult in hyperglycemia and/or DKA. Tubing in currently existing insulinpager pumps extend from the pump housing to the user body insertionsite, thus any air bubbles detector to detect bubbles in tubing needs tobe external to the pump housing or somehow connected to the deliverytube. Typical current skin adherable insulin dispensing devices have noair bubbles detectors.

Leakage from the insulin path is another cause for insulin underdelivery or completely missing delivery. Leakage can be related tocannula dislodgement from the subcutaneous insertion site. Because skinsurface is usually covered by adhesive tape the user cannot see theleaking cannula. Other causes for leakage are related to leakage fromthe insulin delivery tube or tube connectors. Typical current insulinpumps do not have leakage detectors.

To address those drawbacks, a pump with at least two subcutaneouselectrodes monitors a temporary conductivity variation in thesubcutaneous tissue upon drug administration, thus allowing monitoringthe correct execution of each administration.

Therefore, there is a need for a skin adherable infusion device that isinexpensive and that extends patient customization.

SUMMARY

According to the present disclosure, a system and method for determininga flow condition of therapeutic fluid in a two-part portable fluiddelivery device is presented. A first reusable part comprising a rotarymotor and a flow detector is provided. The flow detector comprises atleast one heating element and at least two temperature sensors. A seconddisposable part comprising a reservoir, an exit port, and a deliverytube that communicates between reservoir and exit port is provided. Thefirst reusable part and the second disposable part are paired such thatthe flow detector touches the delivery tube. The heating element, themotor and the as least two temperature sensors are operatedsequentially. The flow condition is determined based on a signalprovided by the at least two temperature sensors.

Accordingly, it is a feature of the embodiments of the presentdisclosure to provide a skin adherable infusion device that isinexpensive and that extends patient customization. Other features ofthe embodiments of the present disclosure will be apparent in light ofthe description of the disclosure embodied herein.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The following detailed description of specific embodiments of thepresent disclosure can be best understood when read in conjunction withthe following drawings, where like structure is indicated with likereference numerals and in which:

FIGS. 1a-c illustrate a schematic diagram of an example therapeutic andmonitoring system that includes a skin securable patch unit and a remotecontrol unit according to an embodiment of the present disclosure.

FIGS. 2a-b illustrate an example skin securable patch unit connected toa skin adherable cradle according to an embodiment of the presentdisclosure. The patch unit may be disconnected from and reconnected to acradle unit and can be comprised of one part (2 a) or two parts (2 b).

FIG. 3 illustrates an example therapeutic and monitoring system thatincludes a remotely controlled patch according to an embodiment of thepresent disclosure.

FIG. 4 illustrates a perspective view of an example therapeutic andmonitoring system with a remote control that includes an integratedblood glucose monitor according to an embodiment of the presentdisclosure.

FIG. 5 illustrates a perspective view of an example two part patch unitand cradle according to an embodiment of the present disclosure.

FIGS. 6a-d illustrate cross sectional views of an example cradle andadhesive after insertion of a tip through a well and into the bodyaccording to an embodiment of the present disclosure.

FIGS. 7a-b illustrate an example disposable part that includes areservoir filled with therapeutic fluid according to an embodiment ofthe present disclosure.

FIG. 8 illustrates a schematic diagram of an example two part patch unitthat includes a reusable part and a disposable part according to anembodiment of the present disclosure.

FIGS. 9a-b illustrate a perspective view of an example embodiment of anunpaired two-part patch unit and a magnified view of a flow detectorwithin the reusable part according to the present disclosure.

FIG. 10 illustrates a flow diagram of an example feedback controlprocedure for operation of a dispensing patch unit according to anembodiment of the present disclosure.

FIG. 11 illustrates a flow diagram of an example “no flow” procedureaccording to an embodiment of the present disclosure.

FIG. 12 illustrates a decision table based summarizing the variousconditions causing no-flow according to an embodiment of the presentdisclosure.

FIGS. 13a-b illustrate a perspective view of the reusable part and amagnified view of the flow detector according to an embodiment of thepresent disclosure.

FIG. 14 illustrates a diagram showing a folded PCB within a reusablepart and electronic components according to an embodiment of the presentdisclosure.

FIGS. 15a-b illustrate a longitudinal cross-sectional view of a patchunit and a magnified view of a flow detector according to an embodimentof the present disclosure.

FIG. 16 illustrates a schematic diagram of a flow detector locatedwithin a reusable part and engaged with a delivery tube that is locatedin a disposable part according to an embodiment of the presentdisclosure.

FIGS. 17a-b illustrate schematic diagrams illustrating operation of aflow detector during no flow, and flow conditions according to anembodiment of the present disclosure.

FIG. 18 illustrates a schematic diagram of a flow detector and some ofelectronic components thereof according to an embodiment of the presentdisclosure.

FIG. 19 illustrates a graph illustrating a heating element/motorsequence of operations and flow patterns in the cases of flow and noflow within the delivery tube according to an embodiment of the presentdisclosure.

FIGS. 20a-b illustrate graphs showing the sequence of heating elementand motor activation according to an embodiment of the presentdisclosure.

FIG. 21 illustrates a graph showing results of a test comparing volumes(Q) of delivered flow measured with a flow detector and with agravimetric scale according to an embodiment of the present disclosure.

FIG. 22 illustrates a view of an example embodiment of a flow detectorwith four thermistors, each of which can serve as a heating element oras a temperature sensor according to an embodiment of the presentdisclosure.

FIGS. 23a-b illustrate views of a disposable part with a flow detectoraccording to an embodiment of the present disclosure.

FIG. 24 illustrates a diagram of a disposable part including a flowdetector, with the chassis and housing connected according to anembodiment of the present disclosure.

FIGS. 25a-b illustrate a flow detector within a reusable part and amagnified view of the flow detector according to an embodiment of thepresent disclosure.

FIG. 26 illustrates a graph of exemplary temperature gradient versustime curves, indicative of a “flow” and a “no flow” condition,respectively according to an embodiment of the present disclosure.

DETAILED DESCRIPTION

In the following detailed description of the embodiments, reference ismade to the accompanying drawings that form a part hereof, and in whichare shown by way of illustration, and not by way of limitation, specificembodiments in which the disclosure may be practiced. It is to beunderstood that other embodiments may be utilized and that logical,mechanical and electrical changes may be made without departing from thespirit and scope of the present disclosure.

The systems, devices and methods as disclosed herein may be particularlyuseful in the context of Diabetes therapy via Continuous SubcutaneousInsulin Infusion (CSH) with the therapeutic fluid being a liquid insulinformulation. However, the systems, devices and methods described hereinare not limited to delivering insulin but, rather, apply to deliveringany other drug and to, optionally, concomitantly monitor analyte. Whenused in the following description, the term “analyte” can mean anysolute composed of specific molecules dissolved in an aqueous medium.

A type of skin adherable infusion devices to alleviate cost issues andto extend patient customization is presented. Such a device generallycan include a remote control unit and a skin securable device/patch unitthat may comprise two parts: a reusable part comprising a drivingmechanism, electronics, and other relatively expensive components and adisposable part comprising a reservoir, and, in some embodiments, apower source (e.g., batteries). The disposable part may also includeother relatively inexpensive components.

The term “disposable” can indicate that the part can be used for alimited application time which can be in a typical range of some days upto e.g. two weeks. Such a disposable part does not include any componentthat requires or generally allows maintenance or repair. The conceptunderlying this device can provide a cost-effective, skin securableinfusion device, and can enable diverse usage through use of variousreservoir sizes, various needle and cannula types, and the like.

Such a pump can be remotely controlled or can be operated by dedicatedcontrol buttons located on the patch housing. For such devices, the usercan deliver a desired bolus dose by repeated pressing the controlbuttons.

The skin adherable insulin pumps may include a continuous glucosemonitor including a glucose sensing mechanism. The subcutaneous cannulaincludes a glucose sensing probe and glucose readings can be displayedon a remote control screen.

Such fluid flow detectors can comprise a heating element and twotemperature sensors. Upon activation of the heating element, a flowcondition of the fluid inside the delivery tube can be determined basedon a signal provided by the temperature sensors. A temperature gradientwithin the therapeutic fluid can be detected. The determined flowcondition can be one of: air bubbles within the delivery tube, occlusionwithin the delivery tube, or leakage within the delivery tube orcombinations thereof. In some embodiments, the therapeutic fluid can beincompressible (i.e. not compressible or with negligiblecompressibility). In this case, the flow condition assessed in thedelivery tube can also be true for (is the same than) the flow conditionin the fluid delivery path situated downstream the delivery tube (anydelivery circuit situated “after” the delivery tube when following theflow direction). For example, if the condition is “no flow” in thedelivery tube, it can mean that there is “no flow” in the cannulaconnected after the exit port of the delivery tube. In other words, thedetermined flow condition associated with the delivery tube can also beassociated with downstream path elements such as the exit port or thecannula.

In one embodiment, a particular portable therapeutic fluid delivery canbe provided in two parts, for example, a reusable and a disposable part.Upon the pairing of these parts, the heating element and the temperaturesensors can touch the delivery tube. The first part can be a reusablepart comprising a driving mechanism, the driving mechanism including arotary motor and at least one gear, and a flow detector. The flowdetector can comprise the at least one heating element, at least twotemperature sensors, and a processor. The second part can be thedisposable part comprising a reservoir, an exit port, and a deliverytube communicating between reservoir and exit port.

Of course, the distribution of components over the two parts can bechanged and/or evolve over time according to different device designs.Generally, the reusable part comprises the most expensive components andthe disposable part the cheapest ones. But various considerations canmodify this choice, having no technical consequences. For example, thebattery or energy source originally thought as disposable can becomerechargeable and can be included in the reusable part. Other grounds orconsiderations can lead to modify this distribution of elements orcomponents over the two parts: business and economic considerations,environmental motivations, manufacturing reasons, user convenience, andthe like. The principle remains that upon pairing of the two (or more)parts, the heating/sensing system can be enabled and when operated, canbe enabled to assess the fluid flow condition. The disposable part andthe reusable part can be designed such that upon pairing of the reusablepart with the disposable part, the at least one heating element and theat least two temperature sensors can touch the delivery tube. Theprocessor, upon activation of the heating element, can detected a flowcondition of the therapeutic fluid inside the delivery tube based on asignal provided by the at least two temperature sensors.

The proposed architecture can allow the more complex components of thedevice and in particular of the flow detector, to be used with a numberof disposable parts in sequence, thus reducing the device and therapycosts as compared to where the complete flow detector or the device aswhile is discarded after some days of application.

In some embodiments, the at least one heating element and the at leasttwo temperature sensors can be arranged on a printed circuit board (PCB)of the reusable part.

In some embodiments, the delivery device can detect a temperaturegradient within the therapeutic fluid and can determine the flowcondition based on the temperature gradient. The temperature gradientmay be determined as temperature difference measured by the at least twotemperature sensors. e.g. an upstream temperature sensor that isupstream of the at least heating element and a downstream temperaturesensor that is downstream of the at least one heating element. Such atemperature difference can serve as estimate for the temperaturegradient inside the fluid.

In some embodiments, the flow condition can comprise at least one of:air bubbles within the delivery tube, an occlusion within the deliverytube, a leakage within the delivery tube or combinations thereof. Thoseflow conditions can reflect defect or other hazardous situations.

In some embodiments, the delivery device can alarm the patient regardingconditions of one or more of: occlusion, air bubbles, and leakage in thedelivery tube.

In some embodiments, the delivery device can comprise a skin securabledrug dispensing unit comprising the reusable part and the disposablepart.

In some embodiments, the delivery device can be remotely controlled.

In some embodiments, the drug dispensing unit can include buttons andthe delivery device can be operated manually by operating the buttons.

In some embodiments, the drug dispensing unit can disconnect from andreconnected to a skin adherable cradle unit.

In some embodiments, the disposable part can include an energy supply.

In some embodiments, the delivery device can include a handheld remotecontrol unit comprising an integrated blood glucose monitor.

In some embodiments, the drug dispensing unit can include a bloodglucose sensing unit.

In some embodiments with a blood glucose sensing unit, the device caninclude one subcutaneous insertable tip that serves both as therapeuticfluid cannula and sensing probe.

In some embodiments, the motor can be a stepper motor. Alternatively,the motor may, e.g., be a standard DC motor or a brushless DC motor.

In some embodiments that include a stepper motor, the delivery devicecan include a pulse generator coupled to the stepper motor to operatethe stepper motor. The delivery device can further detect an occlusionby detecting a mismatch between pulses supplied to the motor and motoroperation. Motor operation may be monitored and determined via arotatory encoder or revolution counter.

In some embodiments, the delivery device can cause power to be deliveredto the at least one heating element; can cause power delivery to the atleast one heating element to be suspended, and can cause power to bedelivered to the motor to begin motor operation subsequent to thesuspension of power delivery to the at least one heating element. Thepower delivered to the motor can cause the heated therapeutic fluid toflow in the delivery tube.

In some embodiments, the delivery device can include a capacitor and apower supply. The delivery device can periodically charge the capacitorvia the power supply and periodically discharge the capacitor byoperating the motor.

In some embodiments that include a capacitor, the delivery device canperiodically discharge the capacitor by powering the at least heatingelement.

In some embodiments that include a capacitor, the delivery device cansequentially discharge the capacitor by operating the motor and poweringthe at least one heating element and recharge the capacitor betweenoperating the motor and powering the at least one heating element.

In some embodiments, the processor can be coupled to the motor. Theprocessor can generate and provide pulses to the motor for powering themotor. The reusable part can include a revolution counter. The devicecan detect an occlusion if the flow detector determines a condition ofno flow in the delivery tube and there is a mismatch between pulsesgenerated by the processor and a predicted number of motor revolutions.

In some embodiments, the delivery device, upon sequential operations ofmotor and flow detector, can detect air bubbles within the delivery tubeand/or an occlusion in the delivery tube.

In some embodiments, the at least one heating element can be proximateto the delivery tube at a first location. The at least one heatingelement can directly heat the delivery tube to cause heating of thetherapeutic fluid in the delivery tube. An upstream temperature sensorcan be upstream of the first location. A downstream temperature sensorcan be downstream of the first location.

In some embodiments, the delivery device can determine flow rate oftherapeutic fluid within the delivery tube based, at least in part, ontemperature measurements measured by the at least one upstreamtemperature sensor and the at least one other downstream temperaturesensor.

In some embodiments, the flow detector can further comprise an alignmentrack. The alignment rack can hold the at least one heating element, theat least one upstream temperature sensor, and the at least onedownstream temperature sensor. The alignment rack can move the heatingelement, the at least one upstream temperature sensor, and the at leastone downstream temperature sensor alternatively to proximate to thedelivery tube, and in contact with the delivery tube.

In some embodiments, the delivery tube can be resilient, i.e. elastic orflexible. Such a delivery tube can have the particular property ofcompensating for tolerances, thus ensuring reliable contact of the tubewith heating elements and temperature sensors.

In some embodiments, the flow detector, in response to a determinationthat there is no fluid flow, can identify one or more of severalpossible problems causing the condition of no fluid flow. The severalpossible problems can include: a missing pulse of the motor operation, areservoir of the therapeutic fluid being empty, presence of air bubblesin the delivery tube, occlusion occurring in the delivery tube and thelike.

In some embodiments, the delivery device can adjust or control deliveryof the therapeutic fluid through the delivery tube based on determinedflow such that the therapeutic fluid can be delivered at a substantiallypre-determined delivery rate.

According to a further aspect, a reusable part for use in a portabletherapeutic fluid delivery device in combination with a disposable partis presented. The reusable part can include a driving mechanism, thedriving mechanism including a rotary motor and at least one gear; a flowdetector comprising the at least one heating element and at least twotemperature sensors, and a processor. The reusable part can pair withthe disposable part such that upon pairing of the reusable part with thedisposable part, the heating element and the at least two temperaturesensor touch a delivery tube of the disposable part. The processor, uponactivation of the at least one heating element, can detect a flowcondition of the therapeutic fluid inside the delivery tube.

According to a still further aspect, a disposable part for use in aportable therapeutic fluid delivery device in combination with areusable part is presented. The disposable part can include a reservoir,an exit port, and a delivery tube communicating between reservoir andexit port. The disposable part can pair with the reusable part such thatupon pairing of the reusable part with the disposable part a heatingelement and at least two temperature sensors of the reusable part cantouch the delivery tube.

According to a still further aspect, a therapeutic fluid delivery devicekit is presented. The kit can include a reusable part and at least twodisposable parts. The reusable part and any of the disposable part canform a skin adherable drug dispensing unit.

In some embodiments, the kit can further include at least two skinadherable cradle units. The drug dispensing unit can disconnect from andreconnected to the cradle unit.

According to a still further aspect, a method for determining a flowcondition of therapeutic fluid in a two part portable fluid deliverydevice is presented. The method can comprise providing a reusable partthat can include a rotary motor and a flow detector. The flow detectorcan include at least one heating element and at least two temperaturesensors. A disposable part can be provided. The disposable part caninclude a reservoir, an outlet port, and a delivery tube that iscommunicating between reservoir and exit port. The reusable part and thedisposable can pair such that the flow detector can touch the deliverytube. The flow detector can operate consecutive to an operation of themotor at a predetermined number of operation cycles. The flow conditioncan be determined based on a signal provided by the at least twotemperature sensors.

In some embodiments, the method can include determining a temperaturegradient within the therapeutic fluid and determining the flow conditionbased on the temperature gradient.

In some embodiments, the method can comprise heating the therapeuticfluid in the delivery tube at a first location. A temperature of thetherapeutic fluid can be measured at least at an upstream location and adownstream location from the first location. A temperature gradient canbe determined within the therapeutic fluid. The flow condition can bedetermined based on the determined temperature gradient.

In some embodiments, the method can, in response to a determination thatthere is no fluid flow, identify one or more of several possibleproblems causing condition of no fluid flow. The several possibleproblems can include a missing pulse of the motor operation, a reservoirof the therapeutic fluid being empty, presence of air bubbles in thedelivery tube, occlusion occurring in the delivery tube and combinationsthereof.

According to a still further aspect, a method for delivering atherapeutic fluid into a patient's body via a portable fluid deliverydevice can comprise determining a flow.

In some embodiments, the method can include delivering power to the atleast one heating element; suspending power delivery to the at least oneheating element; and delivering power to the motor of the pump to beginmotor operation subsequent to the suspension of power delivery to theheating element. The power delivered to the motor can cause the heatedtherapeutic fluid to flow in the delivery tube.

In some embodiments, the method can include adjusting the delivery ofthe therapeutic fluid through the delivery tube such that thetherapeutic fluid can be delivered at a substantially pre-determineddelivery rate.

A method for determining a flow condition or a method for delivering atherapeutic fluid to a patient may be carried out using a deliverydevice. Vice versa, a delivery device may carry out any of the methods.Therefore, any feature or embodiment that is disclosed and discussed ina device context may be used for detailing a corresponding method claimand vice versa.

The processor of a device can be coupled to the motor and can controlits operation. It can be advantageously to be further coupled to theflow detector and can control operation of the flow detector andprocesses and can evaluate the signals provided by the flow detector, inparticular by the temperature sensors. The processor may further be usedfor additional purposes such as controlling a user interface andtelemetry interfaces for communicating with a remote control unit and/orfurther external devices, such as a PC. The term “processor” or,interchangeably, “controller” can be used in the sense of electroniccircuitry that can be typically based on one or microprocessors ormicrocontrollers and/or ASICS. The processor may further include or becoupled to additional circuitry and/or functional units such as powersupply circuitry, safety circuitry, timers, clock circuitryanalogue-to-digital (AD) conversion circuitry, and the like. Theprocessor may be realized by a single or a multiple of distinctcomponents.

Fluid may be administered in a programmed pulsed delivery pattern(hereinafter “delivery pulses” or “delivery pulse mode”-predeterminedquantum (delivery pulse) at every predetermined period, for exampleabout 0.05 insulin units (U) every 30 minutes). Thus, fluid may beadministered in a pulsatile wave form (delivery pulses), thus realizinga quasi-continuous delivery. The delivery pulses can be changed at thepatient's discretion or according to feedback from one of the detectors.The flow detector can determine a flow condition of the therapeuticfluid in the delivery tube. The flow condition may include adetermination whether or not there is fluid flow in the delivery tubeand/or determining a flow as amount per time. The flow condition mayfurther include derived information such as a determination whether ornot a flow is above or below a given flow threshold value.

For embodiments that are based on a pulsed fluid delivery, the flowdetector may measure the volume of fluid or detecting a flow conditionin, for example, each delivered pulse. The data may be used by theprocessor to adjust the volume in each quantum (delivered pulse) and/orthe intervals between delivered pulses based on the received measureddata. Additionally or alternatively, the data provided by the flowdetector may be used for triggering an alarm in case of a defect,malfunction, or hazardous situation, such as air bubbles in the deliverytube, an occlusion or a leakage.

In some embodiments, reservoir can be a cartridge with a displaceableplunger and the motor can be coupled to the plunger via a threaded drivescrew/spindle. The plunger can be displaced in a controlled way similarto a syringe mechanism in response to axial rotation of a threaded drivescrew, resulting from motor operation. In some embodiments, the drivescrew can have a distal end that can be substantially rounded orspherical in shape and can articulate with the plunger and a proximalend that can engage with a rotating gear connected to the motor. In suchembodiments, the plunger can have a distal end which can contact thefluid within the reservoir and at least one gasket to prevent leakage offluid from the reservoir. The plunger may also include a proximal endcomprising a socket that articulates with the rounded distal end of thedrive screw. The socket may be shaped to interact with the distal end ofthe drive screw. A drive nut with internal threads may also be providedfor engagement or disengagement with the drive screw. For example, in anengaged position, rotation of the drive screw within the drive nut canlinearly displace the drive screw and, in turn, the plunger canarticulate therewith. In a disengaged position, the drive screw mayfreely move within the drive nut and can be manually pushed backward forreservoir filling or pulled forward for reservoir priming.

In some embodiments, the device can comprise a two-part skin securabledrug dispensing unit, a skin adherable cradle unit, and a remote controlunit. The drug dispensing unit can be disconnected and reconnected fromand to the cradle unit. A connecting lumen can provide fluidcommunication to a cannula rigidly connected to the cradle unit. Fluiddelivery can be remotely controlled by the remote control unit or,alternatively or additionally, by manual buttons located on thedispensing unit.

The cradle unit may include a flat sheet with an adhesive surface, apassageway for a cannula, and snaps for securing the cannula anddispensing unit. The cannula can include a distal end residing in thebody and a proximal end that may include a self-sealed rubber, thusforming a sealing pierceable septum. The cannula can manually, orautomatically, be inserted into the body using a penetrating member forskin pricking. After insertion, the cannula can be secured to the cradleunit with snaps located near the cradle passageway (cradle and cannulahereinafter “infusion set”). The drug dispensing unit can be connectedand disconnected from the cradle unit. During connection, a connectinglumen within the skin adherable unit can pierce the cannula septummaintaining fluid communication between the reservoir, drug deliverytube, and the body.

Such a configuration including a skin securable dispensing unit and acradle can be particularly convenient and flexible in use. The costs canbe comparatively low due to the partly reusable design. Otherconfigurations however may be used as well. For example, an adhesive padmay be directly provided on the disposable part such that the disposablepart and the reusable part, once paired, can be directly attached to theskin. For such embodiments, the disposable part may include the cannulaor a cannula may be provided separately. Furthermore, the fluid deliverydevice may be carried in a pager-like way rather than attached to theskin and a cannula may be coupled to the device via tubing.

A remote control unit may comprise a handheld device for programmingfluid flows, generally controlling the device, in particular a patchunit, acquiring data, and providing visual and/or audible and/orvibration notifications. In some embodiments, the remote control unitmay include without limitation a wrist-watch, a cellular phone, apersonal digital assistance (“PDA”), an iPhone or iPod, a personalcomputer (PC) or a laptop computer. In some embodiments, the remotecontrol unit may include an integrated blood glucose monitor, such as anoptical refractometer-based or electrochemical blood glucose monitor, asgenerally known in the art. Such monitors can be used in a combinationwith test strips that are typically disposable and single-use.

In some embodiments, the delivery device can include a skin securabledrug dispensing unit which can include a blood glucose monitoring unit.The blood glucose monitoring unit may be based on an electro-chemicalsensing principle as generally known in the art and may accordinglyinclude a corresponding sensing probe.

In some embodiments, the disposable part may contain a power source(e.g., batteries) which may serve as primary power source for the deviceor the application time of the disposable part, i.e., typically somedays. Alternatively or additionally, a power source, typically in formof a rechargeable or non-rechargeable battery, may be included in thedisposable part.

In some embodiments, the reservoir may be a cartridge including aplunger and may have a flat profile (e.g., oval, ellipse, or four oreight arches) to provide a thin configuration as compared to a circularprofile.

In some embodiments, the reusable part and disposable part may each havean external housing (e.g., shell) and an internal structure (e.g.,chassis), where the external housings and internal structures can becoupled when the reusable part and disposable part are connected. Thehousings of both parts may have an opening that provides contact betweendisposable part and reusable part internal structures (chassis).

The delivery tube may be made of a resilient material and may be wrappedaround the disposable part chassis such that a portion of the loop isfacing the reusable part chassis and can contacts the flow detectorincluded in the reusable part. For such an embodiment, connecting orpairing of the reusable part and disposable part can cause thefollowing: 1) the reusable part's and disposable part's externalhousings and internal structures are coupled together, thus resulting inthe drive nut to move from a disengaged position to an engaged positionto thus engage the threads of the drive screw with the threads of thedrive nut, 2) engagement of the proximal end of the drive screw with thegear located within the reusable part, 3) engagement of the deliverytube of the disposable part with the non-disposable components of theflow detector, i.e., the at least one heating element and thetemperature sensors of the reusable part. In embodiments where thedisposable part includes a power supply that also supplies the reusablepart, electrical contact may be established during pairing as well.

The delivery device may, besides the flow detectors, include either ormultiple of the following detectors:

-   -   A motor errors and/or or a motor supervision detector—a detector        designed to perform detection of missing motor train pulses.        This detector may be include a rotary encoder or revolution        counter, e.g. on an optical or magnetic basis.    -   An end of reservoir detector—a detector designed to perform        detection of remaining volume of therapeutic fluid (drug) in the        reservoir.    -   Occlusion detectors (e.g., two detectors)—Such detectors are        designed to perform detection occlusion in drug delivery path.        One detector may be based on counting missing pulses and another        occlusion detector may be based on monitoring flow in the        delivery tube (e.g., using, for example, a flow detector).    -   An air bubbles detector—Such a detector is configured to perform        detection of air bubbles in the drug delivery path.    -   A leakage detector—detection leakage in drug delivery path.

The term “detector” can be used in the sense of a functional unit thatmay include hardware and/or firmware or software based components.Software or firmware based components may be, fully or partly, beimplemented by the processor of the delivery device and/or spatededicated circuitry. Furthermore, detectors may, fully, or partly, makeuse of the same physical sensors.

As described herein, in some implementations detection of occlusion, airbubbles, and leakage may all be based on signals that are provided bythe flow detector.

Two temperature sensors can be located symmetrically, at pre-definedsubstantially equal distance from the heating element (e.g., oneupstream of the heating element, the other downstream of the heatingelement). After connection of the disposable-reusable parts, the heatingelement and temperature sensors (e.g., a resistor that change resistanceaccording to temperature changes, for example a thermistor) can come incontact with the delivery tube in a way that can ensure reliable thermalcoupling. A thermistor or thermal sensor can be a type of resistor whoseresistance varies significantly with temperature, more so than instandard resistors. Most PTC thermistors can be the “switching” type,which means that their resistance rises suddenly at a certain criticaltemperature. Another type of PTC thermistor can be the polymer PTC whichcan have a highly nonlinear resistance/temperature response and can beused for switching, not for proportional temperature measurement. Yetanother type of thermistor can be a silistor, a thermally sensitivesilicon resistor. Silistors operate on the same principles as otherthermistors, but employ silicon as the semiconductive componentmaterial.

Activation of the heating element can cause temperature elevation offluid within a portion of delivery tube that comes in contact with theheating element and consequently formation of an upstream (direction offlow) and a downstream (opposite direction of flow) temperaturegradients. Since thermal coupling of the fluid and the heating elementand temperature sensors can be achieved via the delivery tube, atemperature gradient can also be formed in the delivery tube. Thedistribution of temperature gradient can be related to the drug flowwithin the delivery tube and thus to the flow rate and flow volume(dose). In the absence of fluid flow, the temperature gradient can besubstantially symmetrical relative to the heating element and theelectrical signal from both temperature sensors (e.g.,temperature-sensitive resistors) can be substantially equal (manifestedas equal electrical resistance when temperature-sensitive resistors areused to measure temperature). In the presence of (fluid) flow, thetemperature distribution around the heating element can becomeasymmetric (temperature gradient can be skewed towards the direction offlow) leading to different signals from temperature sensors. Thedifference in signal can be correlated, e.g. in a proportional way, tothe speed of liquid movement (flow). The expected flow rate (in theabsence of any obstruction or leakage) can be determined based, at leastin part, on the known dimensions and physical properties of the deliverytube, thermal energy generated by the heating element, the rate or levelof pumping actuation caused by the pumping mechanism, and the like.

The volume of flow (e.g., drug dose) can thus be derived from, forexample, computation of the area under the curve of time versustemperature differences and/or by evaluating the slope of this curve.Operation of the heating element can be adjusted in an energy savingmode, for example short heating (milliseconds) period that precedesmotor operation by a predetermined time interval and monitoringtemperature gradient for a short period after motor operation. Thedelivered dose can be computed, for example, by the processor of thedelivery device. The result can be used in some embodiments toautomatically adjust motor operation in a positive or negative feedback(more or less motor operation time in one or more consecutive motoroperations).

Occlusion and air bubbles can be detected by the flow detector based ona determination that there is no flow within the delivery tube. If noflow is detected notwithstanding the operation of the motor, the patientmay be, for example, notified to take appropriate remedial action (suchas removing the skin adherable dispensing unit from the cradle unit). Ifair bubbles are visually detected, air purging may be performed and thedispensing unit reconnected. Detection of no flow when the reservoir isfull or partially full and air bubbles are missing can mean that thereis an occlusion within the delivery path and the infusion set (cradleand cannula) should be replaced.

In summary, the flow detector can be used for quantitative measurementand/or for qualitative supervision and monitoring purposes. In the firstcase, the quantitative results may be monitored, and, e.g. stored orlogged in a device memory and/or may be used for closed loop control ofthe delivery device. In the latter case, the evaluation of the flowdetector signal results in a binary signal that can be indicative forthe presence or absence of a defect, malfunction or hazardous situationand can be favorably used for triggering corresponding alarms.

The flow detector data may be evaluated alone and/or may merged andevaluated in combination with signals that can be provided by furthersensors or detectors, such as a rotary encoder or revolution counter.

Referring initially to FIG. 1a . FIG. 1a is a schematic diagram of anembodiment that can include a device 10 for delivering therapeutic fluidinto the body and for monitoring analyte levels within the body and aremote control unit 40 for controlling the device 10 and for dataacquisition. The remote control unit 40 may communicate (via awire-based communication link and/or a wireless communication link) withother external devices such as blood glucose monitors (BGM), continuousglucose monitors (CGM), personal computers (PC), and the like. In someembodiments, the device 10 is realized by a skin securable drugdispensing unit. The drug dispensing unit 10 may include one part (asshown, for example, in FIG. 1b ) or two parts (as shown, for example, inFIG. 1c ). In the latter case, the drug dispensing unit 10 can include areusable part 100 and a disposable part 200. The drug dispensing unitcan include a fluid dispenser that can be operated by the remote controlunit 40 which may, or may not include an analyte monitor, such as ablood glucose monitor. The drug dispensing unit may or may not include ablood glucose measuring unit for continuous or substantially continuousmeasuring the patient's blood glucose level. The drug dispensing unit 10may be programmed with the remote control unit 40 or by using buttonsplaced on the drug dispensing unit (such as a button 15 shown, forexample, in FIG. 2).

Therapeutic fluid (e.g., insulin) can be administered at the followingdelivery patterns:

-   -   1) A bolus dose, which is a dose delivered to counterbalance        meal's carbohydrates consumption and/or high blood sugar. The        pattern of a bolus dose, in particular the distribution of the        delivery over time, can be programmed according to, for example,        glycemic index and fat content of a meal (e.g., after a pizza        meal a dual wave bolus pattern is recommended to immediately        “cover” the fast absorption of carbohydrates and slow absorption        of fat).    -   2) A basal dose or basal rate, which is a substantially        continuous administration of insulin A basal rate may be        provided as a series of pulses of administered insulin to        counterbalance internal glucose production and counter        regulatory hormones (glucagon, adrenalin, etc.). A basal rate        can be changed during the day according to a patient's activity        and hormonal activity. A corresponding time profile, typically a        circadian profile, may be stored in the drug dispensing unit 10        and/or the remote control unit 40.    -   3) A combination of bolus and basal doses. In order to mimic the        normal function of the human pancreas, the drug dispensing unit        10 may be configured to administer insulin basal doses at short        delivery intervals. For example, if the delivery rate is 1.0        units/hour (1 U/h) the patch unit can be programmed to        administer 0.05 U every 3 minutes (20 deliveries/hour), thus 20        consecutive administrations of 0.05 U at intervals of 3 minutes        equals 1.0 U/h.

FIGS. 2a-b show the skin securable drug dispensing unit 10 connected toa skin adherable cradle 20 that can be adhered to skin with an adhesive5. The drug dispensing unit 10 may be disconnected from and reconnectedto a cradle unit 20 and may comprise one part (as shown, for example, inFIG. 2a ) or two parts (as shown, for example, in FIG. 2b ). In thelatter case, the drug dispensing unit 10 can include a reusable part 100and a disposable part 200 as discussed above.

A tip 300 can be provided to deliver fluid (e.g., insulin) into the bodyand/or to monitor analytes (e.g., glucose) within the body. The tip 300may include a cannula for fluid delivery and optionally a probe foranalyte sensing. The tip 300 can be inserted through a cradle openinginto the subcutaneous tissue 6. Commands for dispensing fluid can becommunicated via the remote control unit 40 or by one or more buttons 15located on the patch unit 10. In some embodiments, the buttons mayinclude a bolus button(s) triggering the delivery of a bolus volume offluid (e.g., insulin) into the body.

FIG. 3 is a schematic diagram of an example system. The drug dispensingunit 10 can be secured to a skin adherable cradle 20 connected to skinwith adhesive 5. The patch unit 10 can include a dispensing apparatus1888 for delivery of fluid into the body and a sensing apparatus 1777for monitoring analytes within the body. The dispensing apparatus 1888in particular can include a drive mechanism with gear and a reservoir.The sensing apparatus 1777 may include a blood glucose measuring unit.

Tip 300 can be inserted through passageway in cradle 20 into thesubcutaneous tissue 6. Processor 130 can be provided for one or more ofthe following tasks: 1) to receive analyte readings from the sensingapparatus 1777, 2) to control operation of the sensing apparatus 1888,3) to communicate with remote control unit 40, and 4) to processreceived internal or external data. In some embodiments, the fluid canbe insulin and the analyte can be glucose.

The therapeutic and monitoring system can be operated at either or moreof the following modes:

-   -   1) Closed loop system—the processor 130 can receive glucose        readings from sensing apparatus 1777 and can automatically        control insulin delivery from the dispensing apparatus 1888        based, at least in part, on the received glucose readings.    -   2) Open loop system—the processor 130 can receive glucose        readings from the dispensing apparatus 1777 and can control        insulin dispensing between meals. The processor 130 can also        receive dispensing commands from the remote control 40        (provided, for example, by the user) before meals.    -   3) No linkage between dispensing and sensing apparatuses—glucose        readings can be presented to the user (e.g., via a screen on the        remote control, a screen on the pump). Insulin administration        control commands can be provided (e.g., programmed) via the        remote control unit 40 or buttons on the patch unit (not shown        in FIG. 3).

FIG. 4 is a diagram showing a spatial view of an example therapeutic andmonitoring system. The remote control 40 may include an integrated bloodglucose monitor. The remote control 40 can comprise a screen 41, akeypad 42, and a slot 43 to receive a blood test strip 44.

The remote control 40 can be used for programming the drug dispensingunit 10, acquiring data from the patient, and communicating with otherelectronic devices (e.g., computers) to carry out, for example, datadownloading and uploading. The cradle unit 20 can comprise a flat sheethaving a surface that can be adherable to the skin of a patient. Thecradle unit 20 may also comprise a passageway for inserting a tip 300into the body and protrusions 206 and 207 (e.g., snaps) for securing thepatch unit 10 to the cradle 20. A protrusion 25 (also referred to as a“well”) surrounding the passageway provides rigid connection of the tip300 to the cradle 20. Insertion of the tip 300 may be performed manuallyor via a dedicated inserter.

In some embodiments, a device may include a drug dispensing unit orpatch unit (e.g. an insulin dispensing patch unit) and an analyte sensor(e.g. a continuous glucose monitor as shown in FIG. 4 and describedabove, and may also be disconnected from and reconnected to the body ata patient's discretion.

In some embodiments, fluid may be dispensed according to blood glucoselevels in the body and thus the device may function as an automatic orclosed-loop system. In some embodiments, the device may function as asemi-automatic or open-loop system, where additional inputs from theuser (e.g., meal times, changes in basal insulin delivery rates, orboluses before meals) can be used in a procedure to determine the amountof fluid to be delivered by the device in conjunction with inputs fromthe analyte sensor.

FIG. 5 is a schematic diagram showing a perspective view of the drugdispensing unit 10 and the cradle unit 20. The drug dispensing unit 10can include a reusable part 100 and a disposable part 200 and tworecesses 107 at both sides of the drug dispensing unit 10 (only thefront recess is shown in FIG. 5). Buttons 15 on the reusable part 100can provide insulin delivery programming and administration commandswithout the remote control unit. The disposable part 200 can include areservoir (not shown), an exit port 213, and a connecting lumen 204. Thecradle unit 20 can comprise a flat sheet connected to a skin adherableadhesive tape 5 and snaps 206 and 207. A well 25 can be a protrusionsurrounding a passageway within cradle flat sheet. A tip 300 can beinserted through well 25 and cradle passageway and can rigidly connectto the well 25 after insertion. Insertion can be done manually orautomatically with an inserter device. In some embodiments, duringconnection of the drug dispensing unit 10 and the cradle unit 20, theexit port 213 can align with the well 25 and the connecting lumen 204can pierce a rubber septum located at the proximal part of tip 300providing fluid communication between the reservoir and the tip 300.Snaps 206 and 207 can secure the patch unit 10 within cradle unit 20 byalignment with the front recess 107 and the rear recess (not shown).

FIGS. 6a-d are cross sectional views of a cradle unit 20 and an adhesive5 after insertion of a tip 300 through a well 25 into a body 6 (i.e.subcutaneous tissue). The cradle unit 20 can comprise snaps 206 and 207for securing a patch such as the drug dispensing unit 10 (not shown).

FIG. 6a shows the normal position of tip 300 within the body 6. In thisconfiguration, the tip (comprising a cannula) 300 can be substantiallyperpendicularly positioned within the subcutaneous tissue, providingsmooth fluid delivery.

FIGS. 6b-d show three cannula malfunctions that hamper fluid delivery.In diabetes therapy, the patient insulin should be continuallyadministered and insulin delivery shutdown can cause elevation of bloodglucose, keto-acidosis, and, potentially, death. FIG. 6b shows anocclusion of cannula 300 due to obstruction of foreign material (i.e.dislodged fat tissue, insulin crystallization, etc). FIG. 6c showskinking of cannula 300 that can happened during insertion, for example,when hitting scarred tissue. FIG. 6d shows a complete folding of thecannula 300 underneath cradle 20. This situation can occur duringcannula 300 insertion or if cannula 300 is spontaneously dislodged fromthe body 6 and the patient repositions the cradle 20. All of thosehazardous conditions can be detected by providing a delivery device witha flow detector in accordance with the present disclosure.

FIGS. 7a-b show a diagram of the disposable part 200 that comprises areservoir 222 filled with therapeutic fluid 3 (e.g., insulin). Thedisposable part 200 can include a plunger/piston 240 slideable withinthe reservoir 222 and can force fluid 3 to be expelled from thereservoir 222 into the delivery tube 230 and from the delivery tube 230to an exit port 213. A drive screw 234 can serve as plunger/piston rod.Clockwise or counterclockwise rotation of drive screw 234 can beconverted by nut 233 to forward or backward linear motion. Rotation ofdrive screw 234 can be provided by engagement of a drive screw tip withreusable part gear (not shown) after pairing the reusable and thedisposable parts. In some embodiments, the disposable part 200 caninclude a power source 220 (e.g., one or more batteries). Upon paring,the power source within the disposable part 200 can supply energy to theelectronics components and the motor located in the reusable part. Inother embodiments, the reusable part 100 can include the power source220.

During reservoir filling and/or during operation air bubbles 4 can beformed in the fluid 3 (e.g., oversaturation during refrigeration storageand bubble formation at room or body temperature). FIG. 7b also shows amagnified view of reservoir upper left corner. An air bubble 4 islocated in the reservoir corner and is surrounded with insulin. Furthermovement of plunger/piston can force air bubble 4 into the delivery tube230, potentially resulting in no fluid delivery to the body (air isexpelled instead of insulin). This situation may also be detected by theflow detector.

FIG. 8 shows schematically the two-part drug dispensing unit 10,comprising a reusable part 100 and a disposable part 200. The drugdispensing unit 10 can include a pump for dispensing fluid from areservoir into a patient body. The pump can comprise a driving mechanismthat can include the motor and gear, but may alternatively also includea shape memory alloy actuator, a piezoelectric actuator, and the likeand a pumping mechanism (e.g., a slideable piston/plunger 240). Thepumping mechanism may reside within the disposable part or within boththe disposable and the reusable parts. The reusable part 100 and thedisposable part 200 can include housings (e.g., shell, pocket) 115 and215 respectively and can further include chassis 105 and 205,respectively. After pairing is performed, both chassis 105 and 205 canbe interlocked and both housings 115 and 215 can be interconnected tothus provide sealing. In some embodiments, at least one of the housing115 and the chassis 105 of the reusable part 100 can be connected to atleast one of the housing 215 and the chassis 205 of the disposable part200, upon pairing. The reusable part can include a Printed Circuit Board(PCB) 131 (which can include, for example, a processor-based device andother electronic components), a motor 188, and one or more gears 185,186 and 187. Gear 185 can be, in some implementations, a planetaryreduction gear that rotates spur gear 186. Spur gear 186 can rotate gear187 (hereinafter “rotating sleeve”). The rotating sleeve 187 can have atubular shape with inward longitudinal protrusions (e.g., star shape).Upon engagement of the rotating sleeve 187 with the drive screw(plunger/piston rod) 234, rotation of the sleeve 187 can cause rotationof drive screw 234. In some embodiments, electrical connectors 149 canprovide power to the PCB electronics 131.

In some embodiments, the motor 188 can be a stepper motor. Steppermotors can be widely used in applications requiring accurate positioncontrol and compatibility with digital control systems. Electricalpulses of prescribed pulse width and amplitude can advance the motor bya predetermined distance for each pulse. One standard stepper motor typecan require 20 pulses (20 consecutive pulses or a “pulse train” of 20pulses) for one complete revolution, thus providing 18° of revolutionper pulse. When a pulse train is supplied to the stepper motor, it canrotate substantially continuously at a rate determined by the pulserepetition frequency. One advantage of a stepper motor can be that itsposition can be determined by counting the pulses supplied to it,assuming that no slippage occurs.

In some embodiments, motor energy can be supplied by a capacitor thatcan be recharged between the generations of pulses; energy from one ormultiple batteries can be delivered to the capacitor and in response tocommands/control signals from the processor (e.g., via a pulsegenerator) can discharge the stored energy. A defined pulse train (i.e.20 pulses) can operate (rotates) the motor at defined rotational angle(e.g., 360°) and consequently the motor can rotate the gear (definedreduction ratio. e.g., 1:128). Rotation of the gear can be converted tolinear motion of the piston/plunger causing expelling of a defined fluidquantum (e.g., 0.05 insulin units (U)) from the reservoir into the body.Each quantum of delivered fluid can be defined as a delivery pulse.Consecutive generation of pulse trains can operate the motor for alonger duration (higher rotational angle) resulting in a longer linearmotion of plunger and larger delivery pulses.

To illustrate, consider the following example:

-   -   Pulse trains—3 (3 consecutive 20 pulses)    -   Motor rotation—3 (each pulse train operates motor at 1 full        revolution)    -   Delivery pulse—0.15 insulin units (U). (each motor rotation        expels 0.05 U from reservoir)        Accordingly, in the above example, if a desired basal delivery        rate is 0.1 U/h, the administration cycle is 2 delivery pulses        of 0.05 U every 30 minutes.

The reusable part housing 115 can include one or more buttons 15 foradministration and programming of fluid delivery. The reusable part 100may contain the following sensors: 1) revolutions counter (e.g.,encoder) comprising a rotating pinion 133, a light emitting source(e.g., a LED) 132 a and a light detector 132 b, 2) a sensor fordetection/measurement of flow (flow detector), occlusion (occlusiondetector), and air bubbles (air bubbles detector), which may implementedas a single detector (also referred to as “flow detector “500”, and 3)end-of-reservoir sensor (e.g., located on the gear 187, not shown). Insome embodiments, the flow detector 500 can be used fordetecting/measuring the flow rate of the fluid within the delivery tube230. In other embodiments, the flow detector 500 can be used only fordetermining a condition of no flow or substantially no flow (e.g., as aresult from occlusion, air bubbles, motor malfunction, and the like)

The disposable part 200 can include a power source 220 (e.g., battery),a reservoir 222, a slideable plunger/piston 240, and a plunger/pistondrive screw (plunger/piston rod) 234. The drive screw 234 distal tip cancomprise a drive screw rotator 235. A delivery tube 230 can maintainfluid communication between the reservoir 222 and the exit port 213. Asnoted, in some embodiments, when the reusable part 100 and thedisposable part 200 are paired, the following can happen: 1) thehousings 115 and 215 can connect to provide a sealing, 2) the RP and DPchassis 105 and 205 can interlock, 3) the drive screw rotator 235 canengage with gear 187, 4) battery connectors 149 can connect to thebattery 220 to provide energy to, for example, PCB electronics 131 andmotor operation 188, and 5) the flow detector 500 can contact thedelivery tube 230 to enable flow monitoring of fluid expelling from thereservoir 222 towards the exit port 213.

FIG. 9a shows a perspective view of the unpaired (unmated) two-part drugdispensing unit 10. In some embodiments, the reusable part 100 caninclude optional operating buttons 15, battery connectors 149, aprotective shield 102, and a flow detector 500. The disposable pail 200may include a reservoir 222, a plunger/piston 240, a delivery tube 230,an exit port 213 and a battery 220. FIG. 9b shows a magnified view ofthe flow detector 500. The flow detector 500 can be located, in someimplementations, within the reusable part housing 115 and can include atleast one heating element (heater) 508 and one or more. e.g., two,temperature sensors 502 and 504. In some embodiments, after the reusableand the disposable parts are paired the following can happen: 1) theprotective shield 102 can cover the reservoir 222 providing impact andpressure protection, and 2) the flow detector 500, including the heatingelement 508 and the temperature sensors 502, 504, can contact thedelivery tube 230.

FIG. 10 is a flow diagram of an example feedback control procedure tooperate the dispensing patch unit (e.g., dispensing apparatus of patchunit). An insulin dose can be programmed 602 with, for example, theremote control or buttons on patch unit (programming a dose may includeprogramming of an amount of insulin, e.g., 5 U, a delivery pattern.e.g., dual wave, square wave, etc., and/or duration to be administered).In some embodiments, a pre-determined insulin dose may be pre-programmedinto the patch unit. The programmed dose can be stored in a controlleror processor, which can control 604 motor operations according to thestored programmed dose. In some embodiments, the required dose can bedelivered in sequential pulses of predefined volume (quantum. e.g., 0.05U) at predefined intervals (e.g., 30 minutes).

For example, a required basal delivery rate of 0.1 U/h can be deliveredat delivery pulses of 0.05 U/pulse and an interval of 30 minutes (i.e.,2 per hour). Operation of motor causes plunger movement 605 within thereservoir and consequently insulin can be delivered 606 through adelivery tube. Every motor operation can cause a substantially defineddelivery pulse (volume of fluid) to be expelled from the reservoir.

Flow detection 607 can then be performed by a flow detector (e.g., suchas the flow detector 500 depicted, for example, in FIGS. 9a-b ) that canmonitor insulin flow within a delivery tube during each delivery pulse.In the event it is determined that there is no flow 609 (for example,the motor is activated but flow is not detected because of a motormalfunction, air bubbles, occlusion, etc.), the processor/controller canreceive a negative feedback and several operation can be performed toenable to distinguish between motor malfunction, air bubbles, andocclusion as will be further explained in relation to FIG. 11. In theevent that it is determined that the pump is operating in a normalmanner, and thus flow is detected 608 in the delivery tube, the flowdetector can measure the flow 610 through the tube, according to someembodiments. The processor/controller 603 can receive a positivefeedback and can adjust the flow in the tube based on the measured flowto cause delivery of the insulin (or any other therapeutic fluid) in thetube at a substantially pre-determined flow rate. In some embodiments,the flow can be a pulsatile and the flow detector can detect the flow ineach delivery pulse.

To illustrate feedback control operation as described herein, considerthe following examples:

-   -   1) A bolus of 5.0 insulin units (5 U) is programmed (e.g., at        602 of the procedure depicted in FIG. 10) by the user. The        processor 603 controls 604 (e.g., by sending commands) the motor        to cause it to operate until 5.0 units is delivered. The flow        detector measures delivery of 4.5 U (at 610), and the processor        receives the message that 4.5 U were delivered and controls the        motor to deliver an additional 0.5 units (achieving the        programmed 5 U required dose, 4.5 U+0.5 U=5 U).    -   2) In another example, a bolus of 5.0 insulin units is        programmed (e.g., at 602) by the user, and the processor        controls the motor 604 (e.g., at 604 of the procedure depicted        in FIG. 10) to operate until 5.0 units are delivered. The flow        detector determined a measured delivery of 5.0 U (e.g., at 610)        during motor operation, and the processor receives the message        that 5.0 U has been delivered and causes immediate stoppage of        motor operation.    -   3) In a further example, a basal rate of 1.0 unit/hour (1.0 U/h)        is programmed (e.g., at 602) by the patient. The patch unit        administers (motor operation at each delivery pulse) the 1.0 U/h        basal dose at 3 minutes delivery intervals (i.e. a quantum is        delivered every 3 minutes, 20 per hour) at volume of 0.05 U per        motor operation (0.05 U×20/h=1.0 U/h). In this example, assume        that the measured flow (performed at 610) at one motor operation        is determined to be 0.04 U. The processor receives delivery        input of 0.04 U and controls the motor (e.g., by communication        appropriate control commands/signals) to administer an        additional 0.01 U (0.01 U+0.04 U=0.05 U). If such an adjustment        is made in all motor strokes every 3 minutes for an hour        (precise delivery of 0.05 U every 3 minutes) the total amount of        insulin units (1.0 U) is delivered at 1 hour achieving basal        delivery of 1.0 U/h at extremely high precision.    -   4) In another example, programmed basal delivery rate is 1 U/h        (administered at 0.05 U every 3 minutes). At one motor operation        (delivery pulse) the delivered dose (measured by the flow        detector) is 0.06 U instead of 0.05 U. The processor receives a        signal or message from the flow detector representative of the        measured flow/dose, and controls the motor to deliver 0.04 U in        the next consecutive operation to counterbalance the over        delivery (of 0.01 U) of the previous motor operation.

In embodiments where the flow detector is used only for determining acondition of no flow, no further quantitative evaluation may need to becarried out and the flow detector can serve as a binary sensor. Inembodiments where motor operation is adjusted based on flowmeasurements, quantitative evaluation can be required. Both kind ofoperation may be used either alternatively or in combination.

With reference now to FIG. 11, a flow chart illustrating operation inthe event a “no flow” condition is determined (at 701, corresponding tothe operations 609 shown in FIG. 10, is shown. A “no flow” condition canbe defined as no fluid flow (e.g., insulin is not delivered) within thedelivery tube (such as the tube 230 in FIGS. 8 and 9). This conditioncan happen in, for example, any one or more of the following foursituations: 1) empty reservoir (i.e., no insulin remaining inreservoir), 2) motor or gear malfunction (stuck or broken gear, a motorerror, etc.), 3) occlusion (within the delivery tube, cannula, or at anyplace in the delivery path, and 4) air bubble/s (air can enter reservoirduring filling or pump operation and can occupy a major portion ofdelivery tube). Thus, in the event that no flow is detected by the flowdetector at 701, a set of operations can be performed. Particularly, adetermination 702 can be performed as to whether there is a missingpulse. A missing pulse can be defined as a mismatch between number ofpulses supplied to the motor and the extent (or angle) of revolutions(or number of executed motor steps).

For example, a stepper motor may provide 18° of revolution for eachpulse. Therefore, for a pulse train of 10 pulses motor revolution shouldbe 180°, if motor revolution is less than 180° (e.g., 160°), it canfollow that some pulses were missed (for example, electrical power wasnot converted to motor revolution). Motor revolution can be detected bya revolution counter, such as the one shown and described in relation toFIG. 8. As noted, a situation of missing pulses can occur, for example,as a result of an occlusion, a motor/gear error or because of an emptyreservoir (determined, for example, based on when the piston reaches the“end-of-motion” point). Empty reservoir may also be detected by thecontroller/processor using an end of reservoir sensor signal or bydirect observation of reservoir by the patient. If the reservoir isdetermined to be empty, and thus it can be determined 706 that noinsulin is left in reservoir, the user should replace 707 the emptyreservoir after receiving a corresponding alarm or alert. If it isdetermined that the reservoir is not empty (because insulin is left inreservoir, as may be determined at 703), it can be determined 708 that amotor/gear error 708 has occurred (e.g., due to motor malfunction,broken gear, etc.). To remedy a determination of a motor/gear error, insome embodiments, the reusable part (comprising motor and gear) may bereplaced 709.

If it is determined (e.g., at 701) that there is no flow and it isfurther determined that there are no missing pulses (e.g., at 702), adetermination can be made 704 to confirm or exclude the presence of airbubbles. For example, the patient may visually inspect the device todetermine if there are air bubbles (e.g., upon being prompted a “checkreservoir” alert). A corresponding instruction may be provided to thepatient for example via screen 41 of remote control unit 40. If no airbubbles are detected by the user through direct observation, anocclusion can be determined 712 to have occurred, thus prompting 713 analert/notice that the cannula and/or cradle may need to be replaced(e.g., the infusion site may need to be changed and a new cradle/cannulaset may need to be installed). On the other hand, if it is determinedthat there are air bubbles in the system, air purging may need to beperformed 705, and the pump may need to subsequently be re-operated.

Upon air purging, another determination can be made 710 by the flowdetector to determine if fluid flow can be detected. If there is flow(as indicated by the label “yes” near decision block 710), normaloperation may be resumed 711. If it is determined by the flow detector(at 710) that even after the purging there is still no flow (asindicated by flow-“no” near decision block 710), an occlusion can bedetermined 712 to have occurred and the cannula and/or cradle may needto be replaced 713. Observation of reservoir status (remaining insulin)can be done after disconnection of patch unit from cradle and upondirect inspection of reservoir. After inspection, the patch unit can bereconnected to cradle and operation may be resumed.

FIG. 12 is a decision table summarizing the various conditions causingno-flow. The table lists four situations that may have resulted in “noflow.” and their various indicia (i.e., the various checks anddeterminations based upon which the condition in question may beidentified. In the first situation, the condition of occlusion can bedetermined to have been detected (i.e., to have occurred) when no flowis detected, but—there is no missing pulse, and there is insulin thatremains in reservoir (i.e., the reservoir is not empty). A suitableremedial action when occlusion is determined to have been detected is toreplace the cradle and cannula and have the patch unit (the replaceablepart (RP) and the disposable part (DP) that can include the reservoirwith some remaining insulin) reconnected to a new cradle and cannula. Inthe second situation, the occurrence of air bubbles can be determined tohave been detected when there is no flow, there are no missing pulses,insulin remains in reservoir, and an inspection of air bubbles inreservoir enable the identification of air bubbles. Under thosecircumstances, a suitable remedial action can include purging air andcontinuing normal insulin dispensing operation.

In a third situation, a determination that no insulin remains can bemade when a missing pulse is detected and an end-of-reservoir conditionis detected (e.g., detected using a sensor and/or through a visualinspection). Under these circumstances, suitable remedial action mayinclude replacing the disposable (DP) that contains the reservoir,pairing the DP with a new filled reservoir, connecting the patch unit(with the paired DP-RP) to the cradle, and resuming operation. In thefourth situation listed in the Table of FIG. 12, a motor error can bedetermined to have been detected when a missing pulse is detected and itis determined that insulin remains in the reservoir. Under thesecircumstances, suitable remedial actions can include replacing thereusable part (the disposable part with insulin, the cradle, and thecannula do not necessarily need to be replaced).

With reference now to FIGS. 13a-b , perspective view of the reusablepart 100 (shown in FIG. 13a ) and a magnified view of the flow detector500 (in FIG. 13b ) are shown. The reusable part 100 can comprise areusable part housing 115, a protective shield 102, and one or moreoptional operating buttons 15. In some embodiments, the flow detector500 can be an extension of the Printed Circuit Board (PCB) 512 which mayserve as a base for a heating element (or “heater”) 508 and one or more(e.g., two) temperature sensors 502 and 504. The extension of the PCBcan be part of the detector or, in other embodiments, the extension ofthe PCB can be a separate component to which the detector can becoupled.

In the embodiment shown in FIG. 13 as well as following figures, thetemperature sensors 502, 504 can be arranged such that theirlongitudinal axis can be substantially parallel and can be substantiallyperpendicular to a longitudinal axis of the heating element 508. Inalternative embodiments, the arrangement can be different. In thoseembodiments, any or all of the heating element 508 and the temperaturesensors 502, 504 may be rotated, for example by 90° as compared to theshown configuration. Those configuration changes can particularlyinfluence the sensitivity of the flow detector.

As temperature sensors 502, 504, thermistors may be used in the shownembodiment as well as in embodiments discussed further above and below.Other elements, such as silicone diodes. Schottky diodes, or thermocouplers may be used as well as temperature sensors.

For different reasons, in some embodiments, the heating of thetherapeutic fluid can be as low as possible in accordance with therequired performance of the flow detector. One reason can be the generaldemand for low energy consumption. A further reason can be thesusceptibility of typical drugs, such as insulin, to heating. Favorably,the temperature raise in the fluid can be below 1 Kelvin and may be, forexample, in a range of some 1/1000 Kelvin.

FIG. 14 shows the folded PCB 131 and electronic components. The PCB 131can be a rigid/flexible type with extensions to relevant components. Thefolded PCB 131 can be contained, in some embodiments, within the RPhousing. The PCB 131 can comprise a processor 130, one or more operatingbuttons 15, a light emitting source (LED) 132 a, a light detector 132 b(as shown, for example, in FIG. 8) and an extension 514 and 512 that caninclude the electronic components of flow detector 500. The base of theflow detector 512 (e.g., the PCB extension) can include a heatingelement 508 and two temperature sensors 502 and 504.

FIGS. 15a-b show a longitudinal cross section view (FIG. 15a ) of thedrug dispensing unit 10 and a magnified view (FIG. 15b ) of the flowdetector 500. In the example shown, the drug dispensing unit 10 caninclude a reusable part 100 and a disposable part 200. The reusable partcan include one or more operation buttons 15, a PCB 131 with anextension that can serve as a base 512 for the flow detector 500, amotor 188 and gears 186 and 187. The gears can comprise a 3-stagereduction planetary unit 185 and additional two spur gear units(rotating sleeve). The disposable part can comprise a reservoir 222, aplunger/piston 240, a drive screw (plunger/piston rod) 234, a deliverytube 230, and a battery 220. The flow detector 500 can thus include thebase 512 (PCB extension) as well as a heating element (heater) 508 andtwo temperature sensors 502 and 504. A flow detector engagement rack(hereinafter “rack”) 158 can be connected to the base 512 and may befreely articulated to an engagement rack hub (hereinafter “hub”) 154.The hub 154 can be mounted on a spring 156. Upon pairing of the reusablepart 100 to the disposable part 200, the DP delivery tube 230 can beplaced proximate and, in some embodiments, may come in contact with theheating element 508 and the temperature sensors 502 and 504 mounted onthe PCB base 512. The fully articulated rack 158 (also referred to as“alignment rack”) can provide alignment of the delivery tube 230 withthe heating element 508 and the sensors 502 and 504. The springs 156 canprovide a force applied to the hub 154 and the rack 158 against thedelivery tube 230 and can close the tolerances gaps during DP-RPpairing.

FIG. 16 is a schematic view of one embodiment, wherein the flow detector500 located within the reusable part is placed proximate (or comes incontact with) the delivery tube 230 located in the disposable part. Theflow detector 500 can comprise, or is otherwise coupled to, a supportingblock 152, a hub 154 with a rounded cap 155 (hereinafter “hub cap”), aspring 156, and a flow detector engagement rack 158. In the example, theflow detector 500 can include the PCB extension 514, a PCB base 512, aheating element, and temperature sensors 502 and 504. A batteryconnector 149 can be positioned in the vicinity of the flow detector 500and can provide electrical communication between batteries (not shown)located in the disposable part and the PCB electronics located, in someembodiments, in the RP.

FIGS. 17a-b illustrate the operational principle of the flow detector500, according to some embodiments, when there is no flow, i.e., V=0 (asillustrated in FIG. 17a ) and when there is fluid flow, i.e., V≠0 (asillustrated in FIG. 17b ). The heating element 508 and the temperaturesensors 502, 504 can be located on the base 512 and can be proximate(and may come in contact with, i.e., touch) the delivery tube 230. Thedirection of flow (x) is depicted from left to right. In FIG. 17a ,where there is no flow (V=0), activation of heating element 508 cancause a temperature rise of the fluid within the delivery tube withsubstantially symmetrical (e.g., Gaussian) temperature distribution. Thecurves T can be representative of the temperatures gradient where eachline curve is an isotherm (line of equal temperature). In this scenarioof no flow, both the temperature sensors 502 and 504 can thus sense thesame temperature because the distance between the heating element 508and the sensor 502 can be substantially equal to the distance betweenthe heating element 508 and the sensor 504. Therefore, an equaltemperature detected by both sensors can indicate that there is no flow(V=0).

On the other hand, in FIG. 17b , corresponding to a situation wherethere is fluid flow within the delivery tube 230 (i.e., V≠0). In thisexample, flow can be in the direction of x (V>0). Where there is fluidflow in the opposite direction (−x), the flow can be represented as anegative value, i.e., V<0. During operation of the heating element, thetemperature gradient can be shifted toward the direction of flow and asa result the isotherms can be skewed (they are not symmetrical). Thus,the downstream sensor (the sensor 504 in this example) can sense ahigher temperature than the upstream sensor (the sensor 502 in thisexample). The temperature differences between the sensors and the rateof change of the temperature difference between the sensors, forexample, can be used to determine if fluid actually flows within thetube, and, in some embodiments, to determine the fluid flow rate withinthe tube. Particularly, because the dimensions of the tube 230, thephysical properties of the tube and insulin, and the distance betweenthe heating element 508 and the sensors 502, 504 are all known values,determination of the volume flow rate (which may be represented as Q)can be performed.

FIG. 18 is a schematic diagram with an electrical circuit implementationof the electronic components of the flow detector. The patch unit 10 caninclude a reusable part 100 and a disposable part 200, both includinginterlocking housings that maintain sealing after pairing.

The reusable part 100 can have a protruding part that can include theflow detector 500 which can be received in the disposable part housingsuch that after pairing at least a part of the flow detector 500 can beproximate to, or comes in contact with, the delivery tube 230 of thedisposable part 200. The reusable part 100 can include one or moreoptional operating buttons 15, a motor 188, PCB/electronic components131 that may include a processor 130, and a flow detector power supply(PS) 530.

The disposable part 200 can include a reservoir 222, a delivery tube230, a battery 220, and an exit port 213. Power to the PCB/electronics131 (including to the processor 130) may be supplied from the battery220 located in the disposable part 200. In some alternative embodiments,one or more batteries can reside in the reusable part 100. In someembodiments, the battery 220 may be a rechargeable battery. The heatingelement 508 can receive operation commands and/or control signals from aprocessor-controlled heater driver 534. The driver 534 may be configuredto cause power to be provided to the flow detector to operate thesensors and the heating and to enable controlling the heating duration(for example, 30 milliamps for 30 milliseconds).

In some implementations, the two temperature sensors 502 and 504 can beconnected to a resistor 503 and a tapped resistor (potentiometer) 506 toform a Wheatstone bridge (used to measure an unknown electricalresistance by balancing two legs of a bridge circuit, one leg of whichincludes the unknown component). In a variant, resistor 503 can be atapped resistor (potentiometer), too. The tapped resistor 506 or thetapped resistors 503, 506 may be realized as digital potentiometers withelectronically controlled resistance.

A nominal resistance of each of the temperature sensors 502, 504 may,e.g., be about 10 kOhm in an exemplary embodiment. In this embodiment,resistor 503 may have a value of about 3.24 kOhm. The potentiometer 506may have a resistance that is variable in a range from about 2.68 kOhmto about 3.79 kOhm in this particular example. These values are onlyexamples. Typically, resistance values may range from very low (e.g.,about 10 Ohm) to very high (e.g., about 100 mOhm).

The Wheatstone bridge arrangement can receive electrical current fromthe bridge power supply (e.g., PS 530). As noted, the temperaturesensors can be basically tapped resistors that change the resistanceaccording to temperature change.

The Wheatstone bridge can be supplied by power (PS) and the differencein voltage at two bridge points (V-output) may be compared to thesupplied voltage (V-input). Accordingly, the resistance of the tappedresistors (resulting from temperature change) in the bridge can bedetermined to thus enable derivation of the temperature gradient. Insome embodiments, the temperature sensors can be thermo-resistors (alsocalled thermistors or temperature dependent resistors). Other suitabletemperature sensors can include thermocouples and thermo-elements basedon Seebeck and Peltier effects and semiconductor devices including ofP-N junctions that can have a temperature-dependent current rate, orSchottky. The Wheatstone bridge output signal (voltage difference) canbe determined by the changes of resistance values in the bridge. Adifferential amplifier 532 can amplify the bridge output signals thatare then processed by, for example, the processor 130.

FIG. 19 is a schematic view illustrating motor/heater sequentialoperation and flow patterns in the cases when there is fluid flow andwhen there is no fluid flow within the delivery tube. The X axis candenote time and the Y axis can denotes the flow “pattern”. When there is“no flow”, there can be no significant changes regarding the temperaturegradient or the flow rate. When there is “free flow”, there can bevariations to be detected (the fluid first accelerates because of thepulse given by the motor). Due to high energy consumption of the motorand the heating element (heater), in some implementations, the heatingelement can be operated (to cause fluid warming) before motor operationbegins in accordance with some predetermined time sequence. Heatingtiming and duration (in milliseconds) and motor operation timing andduration may also be pre-determined. Thus, by the time the motor isoperated, a temperature gradient can have already been established andflow movement can shift isotherms to a skewed shape as shown, forexample, in FIG. 17b . The two curves in FIG. 19 show a typical flowversus time patterns in cases of “no flow” and “free flow” conditions.Motor operation can drive fluid from the reservoir through the deliverytube and the flow detector determines/measures flow by integrating thedifferences between the temperature sensors (e.g., V-output in theimplementation of FIG. 18) during a predefined measurement period (forexample, several seconds. e.g., 1-2 seconds) at a pre-determined numberof measurements (for example, between 2-1000 times during themeasurement period) The integral (area under the time/flow curve duringpredetermined time) may then be computed. Operation of the heatingelement followed by motor operation and a predefined measurement periodcan be referred to as a “measurement cycle.” Alternatively oradditionally, the slope of a temperature (or temperaturegradient)-versus-time curve can be evaluated as will be discussedfurther below in more detail.

The evaluation can thus be used for either or more of the followingpurposes:

Flow measurement—the volume of fluid emerging from the reservoir at eachmotor operation and/or at predefined number of motor operations (e.g.,10 consecutive operations) and/or at predefined operation times (e.g.,total motor operations during a 1 hour period) can be measured. Flowmeasured by the flow detector can be used to calibrate the pump(calculating the ratio of motor cycles and volume of expelled fluid.i.e., the K value) during priming. Calibration of the pump may otherwisebe carried out at the manufacturing facility, or periodically, e.g.,according to a predetermined time schedule. Calibration of the flowdetector can be done in the manufacturing facility by comparing flowmeasured by the flow detector to the actual flow (measured, for example,by a gravimetric procedure, i.e., weight of expelled volume).Leakage detection—in the event of a downstream leakage (leakage in thedelivery path occurring after the contact point between the deliverytube and the flow detector), the pattern of time/flow curve can change.The change can be related to reduce resistance which can result in aflow pattern change. The patient can receive a notification on possibleleakage and can take appropriate remedial actions, for example,performing an inspection of the infusion site.

To illustrate uses of the above described measurement procedure(including computing the time/flow integral), consider the followingexamples.

-   -   As noted, in some implementations, the procedure may be used to        perform quantitative flow measurement. For example: The fluid        can be rapid acting insulin (100 units/mL of insulin analogs        Aspart, Lispro, or Glulisine),    -   The pump can be preset at basal rate of—1 U/h    -   Motor operation mode preset—0.05 U every 3 minutes (20        operations/h=1 U/h)    -   Flow detector measured volume at each motor operation is 0.5 mm³        or 0.05 U and total volume during a 1 hour period (20 motor        operations×0.05 U) is 1 U.

This value can be used by the controller/processor to adjust theprogrammed value, as illustrated, for example, in FIG. 10. For example,if the programmed value (in this case basal rate) is 1 U/h and thecalculated integral value is 0.9 U/h, the controller/processor can senda control command to the motor to cause it to deliver an additional 0.1U (0.9 U+0.1 U=1.0 U).

As noted, in some implementations, the procedure may be used tofacilitate calibration in a manufacturing facility. For example, duringa one (1) motor cycle (20 pulses×18°/pulse=360°), the gravimetricmeasurement can be determined to be 1 U, while the flow volume measuredby the flow detector is 0.9 U. Accordingly, the flow detector may bereset so that the flow detector's measurement value is corrected to 1U/cycle.

In some implementations, the procedure may be used to performcalibration during priming. For example, priming may be preset to 1 U(after the DP-RP pairing and air purging, motor can be operated andinsulin can drip from the exit port) and the flow detector can measure0.9 U. In this case, the controller (processor) may reset the K value(ratio between the motor cycle and expelled volume) such that a desiredinsulin volume of 1 U can match the actual delivered 1 U.

As noted, the systems, devices, and methods described herein may be usedto enable occlusion detection. For example, a predefined value of thetime/flow curve integral can be used as a cutoff value to determinewhether there is occlusion (i.e., perform a Yes/No occlusion decision).Calibration of the flow detector (defining the cutoff value) can be doneduring priming. After a few motor rotations (allowing compensation forsystem loading), the processor can compute the area under the time/flowcurve during no occlusion condition. This value (minus a predefinedcushion) can serve as a cutoff value (occlusion threshold) for “noocclusion”. This procedure can be repeated more than one time (e.g.,3-10) and the average value may be used as the selected cutoff/thresholdvalue. Motor rotation can be monitored with a revolution counter (motorcycle encoder) as shown, for example, in FIG. 8, and as described inrelation thereto.

In one example, priming can be set to one (1) motor cycle (3600rotation) that can be equal to 1 U (one insulin unit). The cutoff value(occlusion threshold) can be set to 0.8 U. If, during normal operation(insulin is delivered to subcutaneous tissue), after 1 motor cycle theflow detector measures less than 0.8 U, occlusion can be for exampledeemed to have occurred and the occlusion alarm can be activated.

As noted, detection of “no flow” can mean occlusion, air bubbles, motorerror, or end-of-reservoir (empty reservoir). A procedure toidentify/distinguish between these conditions is described herein inrelation to FIG. 10.

The following are examples of energy saving procedures during variousoperation modes. For a low basal rate (0-1 U/hour), the motor can beoperated at a time interval 3 minutes for example (i.e., more than 3minutes between motor operations). The processor may operate ameasurement cycle during every motor operation (where every motoroperation may be preceded by a heating operation and followed by ameasurement cycle).

For a high basal rate (>1.1 U/hour), the motor can be operated at a timeinterval≤3 minutes for example (i.e., less than 3 minutes between motoroperations). In this situation, the processor may operate a measurementcycle only at the last motor operation in the 3 minutes time interval.

For a small bolus (<0.5 U), the motor can be operated every second, forexample. In this situation, the processor can operate a measurementcycle at the first and last motor operations.

For a large bolus (>0.5 U), the motor can be operated every second forexample. In this situation, the processor can operate a measurementcycle at the first, middle and last motor operations (e.g., bolus 5 U,measurement cycle at 1^(st) motor operation, after 2.5 U, and at lastmotor operation).

FIGS. 20a-b show a heater and motor activation sequence. In someembodiments, the power supply to power the heating element and the motormay be one or more capacitors (e.g., a battery charges the one or morecapacitors and the one or more capacitors discharge the supplied energyto cause motor and heating element operation). FIG. 20a shows a typicaltime sequencing of a heater operation followed by capacitor charging,followed by motor operation, followed by another cycle of capacitorcharging. In the event of a pulse train (more than one sequentialpulses), one heating element operation can be followed by a sequence ofmotor operation-capacitor charging.

FIG. 20b shows a pattern of voltage (or current) versus time curve overfor a capacitor used to power the motor and/or heating element. Duringthe heating operation, the capacitor can be discharged so as to supplycurrent to the load (e.g., the heating element). In this example, theheating time can be 100 milliseconds. Following heating operation, thecapacitor can be recharged and the motor can be operated by anothercycle of capacitor discharge. In this example, the motor operation canlast approximately 20 milliseconds.

FIG. 21 is a graph showing the results of experimental tests comparingvolumes (Q) of delivered flows. The x-axis can be the flow volumemeasured with the flow detector and the y-axis—is the flow volumemeasured by a gravimetric method (e.g., weighted volume of expelledfluid with high sensitive scale). As shown in the graph, there can be acorrelation or at least a strong agreement between the flow detectormeasurements (according to the present disclosure) and the scalemeasurements.

FIG. 22-25 show other examples of a flow detector 800 including fourthermistors according to one embodiment (more or less thermistors ortemperature sensors can be implemented).

FIG. 22 shows the four thermistors 802, 803, 804, 805, each of which mayserve as a heating element and a temperature sensor. The fourthermistors can be in proximity or in contact with the delivery tube230, thus providing good thermal coupling. According to otherembodiments, the thermistors can be mounted, molded, glued, inserted orthe like at the proximity and/or in and/or on and/or within the deliverytube. Thermistors of particular shapes (for example curved to spouse thetube) can also be used in order to improve the accuracy of measurements.Particular placements of sensors also can improve measurements.

FIG. 23a-b shows one embodiment where the disposable part 200 caninclude a housing (pocket) 215 and a chassis 205. The chassis can anchora plunger/piston 240, a drive screw (plunger rod) 234 and a deliverytube 230. FIG. 23 b shows a magnified view of an example of a flowdetector 800 that can detect flow within the delivery tube. In oneembodiment, the flow detector 800 can be attached to the chassis of thereusable part and can comprise four thermistors 802, 803, 804, and 805.

FIG. 24 shows the disposable part 200 that can comprise a reservoir 222,a delivery tube 230, a chassis 205, and a drive screw/piston rod 234.The flow detector 800 can be contained within the reusable part. Uponthe pairing of reusable part and disposable part, the flow detector 800can come in contact with the delivery tube 230.

FIG. 25a-b shows the reusable part 100 that can comprise a chassis 105,a housing 115, one or more operating buttons 15, battery connectors 149,and gears 186 (planetary) 187 (rotating sleeve). FIG. 25b shows amagnified view of flow detector 800 connected to the base 142 andcomprising thermistors 802, 803, 804, and 805.

In one embodiment, the temperature sensors can be located in thereusable part. These sensors elements can be rather expensive. The useof the heat coming from the PCB can render this arrangement useful.Nevertheless, in some embodiments, the temperature sensors can belocated in the disposable part. According to yet another embodiment, thesensors can be present in both parts (distributed over the two parts,either symmetrically or asymmetrically). The temperature sensors caneven be located in a third external part provided the external part cancome close or in contact with the tube at one or another placement alongthe tube (for example, the temperature sensing part can be part of achip or of a “cartridge” or of an insertable element, adapted to come incontact with the tube when inserted into the pump housing).

In general, several couples (or sequences) of heating element(s) andtemperature sensor(s) can be implemented, so that verifications andoptimizations can be handled. Different combinations or sequences can bethus be made. For example a “failsafe” arrangement would comprise oneheating upstream and two sensors downstream (spaced by a few millimetersfor example). The arrangement also can be repeated (one heatingelement—one sensing element followed by one heating element—one sensingelement again).

The fluid (increasing the temperature) can be heated. Cooling the fluid(decreasing the temperature, by heat pump, for example by vapor(de)compression cycles) can provide the same effects and possibilitiesas described herein. A further (and symmetrical) embodiment can thuscomprise in dissipating the heat of the fluid (decreasing thetemperature of the fluid) and can measure the temperature distributionaccording to the same principle described herein.

The fluid circulating in the device can be managed. Data collected bysensors (for example temperature sensors) can be interpreted and thereality of the flow of the fluid in the device can be assessed orcontrolled.

One or more relationships between the fluid temperature and the fluidflow can be established. Such assessments can enable the control of thefluid flow and in particular can allow an enhanced regulation of thedevice. The changes in fluid temperatures can be done in an economicallyway (cheap heating source) or by using existing sources of energy(derivation of energy from the battery for heating) or by re-usingalready emitted energy (in one example, from the PCB unit). The energymanagement can be optimized.

In one example of the particular relation of “energy” with “information”(thermodynamics laws) can be illustrated. As disclosed, the arrangementcan “re-use” the wasted energy in the device (i.e. the PCB) in order toenable the operation of a sensing circuit (information), leading in turnto a better management of the device. This cycle can lead to a saving ofmore energy. At a certain stage, an optimum/equilibrium can be reached.

FIG. 26 illustrates a further embodiment of a method for distinguishingbetween alternative conditions “flow” and “no flow” following motoroperation. The method may be implemented in a fluid delivery device,e.g. by corresponding firmware code executed by processor 130.

The two curves 615, 620 as shown in FIG. 26 can each represent atemperature gradient, given by a temperature difference between thetemperatures as measured by flow sensors. 502, and 504 over time. Thetemperature difference can be expressed in Analogue-to-Digital (ADC)converter values. Curve 615 can represent the “now flow” condition whilecurve 620 can show the “flow” condition. The flow detector design may bedesigned as discussed above with reference to FIG. 13 and following.This design can be assumed in the following for exemplary purposes.

At the beginning, some offset can be present which can be design-givenand may be adjusted by electric calibration via tapped resistor 506 ortapped resistors 503, 506 in general accordance with FIG. 18. The offsetmay be selected such that that the dynamic range of the analogue/todigital converters can be approximately maximum. Upon a heating phase605 in which heating element 508 is activated, the fluid temperature canincrease. Since no flow is present at this point in time, thetemperature distribution along the delivery tube can generally followsFIG. 17a as discussed above. Due to some design-given asymmetry of flowdetector 500, in particular somewhat different thermal environments forthe temperature sensors 502, 504 (as determined, e.g., by surroundinghousing components, further electronic components, and copper-basedconductive paths), the temperature gradients can increase.

After an exemplary time delay of about 1 second, the motor can beoperated. In the case of flow, the heated fluid in the delivery tube inthe area of flow detector 500 can be delivered to the exit port andsubstituted by following non-heated fluid, resulting in the temperaturegradient decreasing, curve 620. In the case of “no flow”, in contrast,the heated fluid in the area of the flow detector 500 cannot besubstituted by following non-heated fluid. Accordingly, the temperaturegradient can decrease only slowly as heat is lead away via thermalconductivity and/or radiation, curve 615. It can be seen that the slopeof curve 615 can be significantly smaller as compared to curve 200.

Therefore, the slope of the temperature gradient as function of time maybe used for distinguishing between “flow” and “no flow” conditions,e.g., by comparing a numerically computed slope value with a thresholdslope. Slope computation can be carried out using two or any largernumber of samples and generally known numerical algorithms. A portabletherapeutic fluid delivery device with a flow detector can comprise aheating element and two temperature sensors. Upon activation of theheating element, a flow condition of the fluid inside the delivery tubecan be determined based on a signal provided by the temperature sensors.A temperature gradient within the therapeutic fluid can be detected. Thedetermined flow condition can be one of: air bubbles within the deliverytube, occlusion within the delivery tube, or leakage within the deliverytube. The device can be in two parts, for example with a reusable and adisposable part. Upon the pairing of these parts, the heating elementand the temperature sensors can touch the delivery tube. Otherembodiments relate to alarms, integration of a blood glucose sensingapparatus, occlusion detection, suspension of motor power, analysis ofmotor revolutions, and use of a plurality of sensors.

Various features and functions of embodiments may be realized in digitalelectronic circuitry, integrated circuitry, specially designed ASICs(application specific integrated circuits), computer hardware, firmware,software, and/or combinations thereof. These various embodiments mayinclude one or more computer programs that can be executable and/orinterpretable on a programmable system including at least oneprogrammable processor, such as a micro controller, which may be specialor general purpose, coupled to receive data and instructions from, andto transmit data and instructions to, a storage system, at least oneinput device, and at least one output device. Some embodiments caninclude specific “modules” which may be implemented as digitalelectronic circuitry, integrated circuitry, specially designed ASICs(application specific integrated circuits), computer hardware, firmware,software, and/or combinations thereof.

These computer programs (also known as programs, software, softwareapplications or code) can include machine instructions for aprogrammable processor, and may be implemented in a high-levelprocedural and/or object-oriented programming language, and/or inassembly/machine language. As used herein, the term “machine-readablemedium” can refer to any computer program product, apparatus and/ordevice (e.g., magnetic discs, optical disks, memory, Programmable LogicDevices (PLDs)) used to provide machine instructions and/or data to aprogrammable processor, including a machine-readable medium thatreceives machine instructions as a machine-readable signal. The term“machine-readable signal” can refer to any signal used to providemachine instructions and/or data to a programmable processor.

Some embodiments may be implemented in a computing system that caninclude a back-end component (e.g., as a data server), or that caninclude a middleware component (e.g., an application server), or thatcan include a front-end component (e.g., a client computer having agraphical user interface or a Web browser through which a user may), orany combination of such back-end, middleware, or front-end components.The components of the system may be interconnected by any form or mediumof digital data communication (e.g., a communication network). Examplesof communication networks can include a local area network (“LAN”), awide area network (“WAN”), and the Internet.

The computing system may include clients and servers. A client andserver can generally be remote from each other and can typicallyinteract through a communication network. The relationship of client andserver can arise by virtue of computer programs running on therespective computers and having a client-server relationship to eachother.

It is noted that terms like “preferably,” “commonly.” and “typically”are not utilized herein to limit the scope of the claimed embodiments orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed embodiments.Rather, these terms are merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment of the present disclosure.

For the purposes of describing and defining the present disclosure, itis noted that the term “substantially” is utilized herein to representthe inherent degree of uncertainty that may be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation may vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

Having described the present disclosure in detail and by reference tospecific embodiments thereof, it will be apparent that modifications andvariations are possible without departing from the scope of thedisclosure defined in the appended claims. More specifically, althoughsome aspects of the present disclosure are identified herein aspreferred or particularly advantageous, it is contemplated that thepresent disclosure is not necessarily limited to these preferred aspectsof the disclosure.

1. A portable therapeutic fluid delivery device for delivering atherapeutic fluid into a body of a patient, the fluid delivery devicecomprising: a first part which comprises: a driving mechanism, aprocessor, a flow detector comprising two electronic componentselectrically coupled to the processor; and a second part whichcomprises: a reservoir, an exit port, and a delivery tube communicatingbetween the reservoir and the exit port, wherein the first part and thesecond part are designed such that upon pairing of the first part withthe second part, the two electronic components of the flow detector arethermally coupled to the delivery tube, and upon activation of a firstone of the two electronic component to heat the delivery tube, theprocessor is configured to determine flow condition of the therapeuticfluid inside the delivery tube based on sensed temperature provided tothe processor by a second one of the two electronic components.
 2. Thefluid delivery device according claim 1, wherein the delivery deviceadjusts or controls delivery of the therapeutic fluid through thedelivery tube based, at least in part, on the determined flow rate suchthat the therapeutic fluid is delivered at a pre-determined deliveryrate.
 3. The fluid delivery device according claim 1, further comprisinga motor, wherein the processor controls the motor to keep delivery ofthe therapeutic fluid through the delivery tube at a pre-determineddelivery rate.
 4. The fluid delivery device according claim 1, furthercomprising a motor, wherein the processor controls the motor to keepdelivery of the therapeutic fluid through the delivery tube at apre-determined delivery rate based, at least in part, on the determinedflow rate.
 5. The fluid delivery device according claim 1, wherein thefirst one of the two electronic components is a heating element and thesecond one of the two electronic components is a temperature sensor. 6.The fluid delivery device according claim 1, wherein the second one ofthe two electronic components is a temperature sensor selected from atemperature-sensitive resistor, a thermistor, and a silistor.
 7. Thefluid delivery device according to claim 1, wherein the flow conditionincludes at least one of: air bubbles within the delivery tube, anocclusion within the delivery tube, a leakage within the delivery tube,or combinations thereof.
 8. The fluid delivery device according to claim1, wherein the fluid delivery device alerts the patient to conditions ofocclusion, air bubbles, leakage in the delivery tube or combinationsthereof.
 9. The fluid delivery device according to claim 1, wherein thefluid delivery device is remotely controlled.
 10. The fluid deliverydevice according to claim 1, wherein the fluid delivery device comprisesa skin securable drug dispensing unit, the drug dispensing unitcomprises the first part and the second part.
 11. The fluid deliverydevice according to claim 1, wherein the fluid delivery device comprisesa blood glucose sensing apparatus.
 12. The fluid delivery deviceaccording to claim 1, wherein the fluid delivery device comprises a skinsecurable drug dispensing unit comprising buttons, and wherein the drugdispensing unit is operated manually using the buttons.
 13. The fluiddelivery device according to claim 1, wherein the fluid delivery devicedisconnects from and reconnects to a skin adherable cradle unit.
 14. Thefluid delivery device according to claim 1, wherein the first part orthe second part comprises an energy supply.
 15. The fluid deliverydevice according to claim 1, further comprising a handheld remotecontrol unit which comprises an integrated blood glucose monitor. 16.The fluid delivery device according to claim 1, further comprising asubcutaneous insertable tip, wherein the subcutaneous insertable tipserves both as a therapeutic fluid cannula and a sensing probe.
 17. Thefluid delivery device according to claim 1, wherein the drivingmechanism comprises a motor.
 18. The fluid delivery device according toclaim 17, further comprising a pulse generator coupled to the motor tooperate the motor, wherein the fluid delivery device detects anocclusion by detecting a mismatch between pulses supplied to the motorand motor operation.
 19. The fluid delivery device according to claim17, wherein the fluid delivery device is configured to deliver power tothe first one of the two electronic components, suspend power deliveryto the first one of the two electronic components, and deliver power tothe motor to begin motor operation subsequent to the suspension of powerdelivery to the first one of the two electronic components.
 20. Thefluid delivery device according to claim 17, further comprising acapacitor and a power supply, wherein the fluid delivery device isconfigured to periodically charge the capacitor via the power supply andperiodically discharge the capacitor by operating the motor.
 21. Thefluid delivery device according to claim 20, wherein the fluid deliverydevice is configured to periodically discharge the capacitor by poweringthe first one of the two electronic components.
 22. The fluid deliverydevice according to claim 1, further comprising a revolution counter anda motor operably controlled by the processor, wherein the processorprovides pulses to the motor to power the motor, and wherein the fluiddelivery device detects an occlusion if the flow detector determines acondition of no flow in the delivery tube and there is a mismatchbetween pulses generated by the processor and a predicted number ofmotor revolutions from the revolution counter.
 23. The fluid deliverydevice according to claim 1, wherein the delivery tube is elastic orflexible.
 24. The fluid delivery device according to claim 1, whereinthe delivery device, in response to a determination that there is nofluid flow, is configured to identify one or more of several possibleproblems causing the condition of no fluid flow, the several possibleproblems comprise a missing pulse of motor operation, a reservoir of thetherapeutic fluid being empty, presence of air bubbles in the deliverytube, occlusion occurring in the delivery tube and combinations thereof.